Is Big Pharma good for your health?

Does research & development (R&D) work in the best interests of patients, of us all? Or does it work in the best interests of shareholders and executive pay? My experience with my son Daniel led me to the conclusion that, all too often, the pharmaceutical industry, or Big Pharma is not good for our health.

Hoffman La Roche (more commonly known simply as Roche), one of the biggest drug companies in the world, refused to allow Daniel onto a clinical trial which might just have saved his life. In my opinion, its refusal was without good reason. But our unfortunate experience is just the tip of a much larger iceberg.

This blog, and those which follow, is intended to spark a debate about the role the pharmaceutical industry plays in the development of new treatments. It need hardly be said that the issue is of crucial importance to humankind. It is not a new debate: I am not the first to harbour serious reservations about the power which Big Pharma wields. I believe we need a fundamental shift in the way R&D is funded.

There are others far better placed than me to support the arguments with empirical evidence.[1] The advantage I have is that I can speak from personal experience. In Daniel My Son, I relate the frustrations we encountered with Roche, an experience which also soured relationships with his oncologist, who I felt was not ready enough to challenge the company.

At that time, around 2008, there was quite some excitement in the world of Ewing’s sarcoma (Daniel’s cancer) about a class of drugs called IGF inhibitors. IGF stands for insulin growth factor. The inhibitors block a pathway known as IGF1R receptors along which the cancer, like many others, likes to travel. Block the pathway and you stop the cancer from spreading: that was the hypothesis. It is spreading cancer which usually kills, as vital organs are invaded.

I had read about IGF inhibitors during my research into Daniel’s illness. They had been around for some time but preliminary results of new clinical trials had shown considerable promise with Ewing’s patients. It was still early days, but there had been so little progress with metastatic Ewing’s – i.e. where the cancer has already spread by the time of diagnosis – that any glimmer of hope quickly magnified into a shaft of optimism.

Daniel’s doctor, Colin McMaster, had not mentioned IGF inhibitors to us. There was a good reason for this. Like nearly all experimental cancer treatment, they were only given when a patient had relapsed – in other words, where he or she has gone into remission but the cancer then reappears. New treatments are first tested on relapsed patients to see if they have any impact on the returning cancer. If they do, and if they prove reasonably safe, they may then be tried out as part of frontline treatment. Frontline treatment, as the term suggests, is treatment given to patients when they first get cancer. Few new therapies in fact make it to the frontline, because they do not work well enough, or are too toxic, when trialled in relapsed patients.

The point was that Daniel at this stage was in remission. He had not relapsed. Experimental treatment such as IGF inhibitors were therefore not on Colin’s radar. That is why he had not told us about them.

However, I was really keen to find something for Daniel while he was in remission. Remission is, in fact, a misleading word. It does not mean that a patient has no cancer left, as one might assume, but rather that he or she has no detectable cancer. That is very different. Diagnostic techniques have improved dramatically but they can still only pick up cancer when it gets to a certain size. The overwhelming probability was that Daniel, after his frontline treatment, still had cancer, even though it could not be detected by scans or blood tests. In other words, there was probably microscopic cancer remaining in his body.

It is the received wisdom of oncology that the best, often the only, time to strike cancer is when it is small and at its earliest stages of development. Not only is it then weaker but also it has not had a chance to mutate. Mutation means change in structure. Chemotherapy and radiotherapy, which are often able to kill enough early-stage cancer cells, usually cannot cope with mutating cancer. Mutation is more likely on relapse.

So, naturally, I wanted to hit Daniel’s residual cancer before it grew sufficiently large to be visible on scans. By that time, it would probably already have mutated and be too difficult to treat. I spoke to many doctors around the world who agreed that this approach made sense. Colin agreed with it as well.

The problems were twofold. First, was there a treatment which stood a chance of working on residual cancer? I thought that IGF inhibitors might be such a treatment, and the great thing about them was that, as far as anyone could tell, they seemed to be pretty safe and not make patients feel ill – in each case a rarity with cancer treatment. The second problem was that, as an experimental treatment, they were only available after relapse.

There were a number of clinical trials for different IGF inhibitors. I looked at them all but the one I focused on was Roche’s. It was known as R1507 (drugs usually don’t have a name before they get regulatory approval). It seemed to have the most promising results. Clinical trials are something of a legal minefield. I discuss how they work and some of the ethical issues around them in Daniel My Son.

Roche had several trials for R1507 on the go, at various stages. The trials were multinational. Clinical trials always have eligibility criteria. Criteria can be positive or negative. An example of a positive criterion is ‘The patient must have relapsed’. An example of a negative criterion is ‘The patient must not have heart disease in addition to cancer’. The criteria also include the type of illness, its extent, the number of relapses, age, gender and so forth. Children are often excluded from trials, a particular concern given that Ewing’s is overwhelmingly a paediatric cancer. So are older people, because they are more likely to have other conditions as well, or to die before useful data can be obtained from them. The world of clinical trials can be ruthless.

Amongst many other requirements, each of the R1507 trials stipulated that a patient must have ‘measurable disease’ to qualify. This meant that cancer had to be visible on scan – in other words, the patient could not be in remission. This is a routine requirement with experimental cancer treatments. The rationale is easy to understand: the drug company wants to know if the treatment works and the easiest way to assess this is to compare a patient’s cancer before and after treatment, and the easiest way to do that is to look at scans to see whether a tumour shrinks.

However, scans are not the only way of detecting cancer. One of the other methods is something called RT-PCR. Ewing’s sarcoma is thought to start in the bone marrow. RT-PCR is a special technique which can detect cancer in the bone marrow (or sometimes in blood), when it is below the radar of scans – in other words, when it is microscopic. It is not a perfect technique and at this time was itself experimental, but studies in France and Israel, and the experience of Ewing’s doctors in Spain, showed a real link between a positive RT-PCR result and relapse with Ewing’s. Positive in this context is a bad thing: it means that the test has detected cancer.

With great difficulty, we managed to have an RT-PCR done of a sample of Daniel’s bone marrow in the UK when he was in remission and this seemed to show that he still had cancer in his marrow. This made it all the more important that he had treatment before the cancer grew to be visible by scan, which would constitute a relapse.

The book relates how I tried to persuade Roche to allow Daniel onto an R1507 trial. The argument, in short, was that RT-PCR positivity was an equivalent benchmark to visibility on scan. One could assess, by repeating the RT-PCR, whether the drug was having an effect, in a similar way to repeating a scan. The information would be of real benefit to Roche, especially given the dearth of data with metastatic Ewing’s.

I also argued that, in fact, Daniel already qualified for the trial. This was because the eligibility criteria referred to ‘measurable or evaluable’ disease. I maintained that the RT-PCR result showed that Daniel did have evaluable disease, even though he did not have disease measurable by scan. I found out that other trials sometimes used RT-PCR positivity as the benchmark, rather than scans. I realised that it was easier for Roche to interpret their eligibility criteria in a way which benefited patients in Daniel’s position, rather than change the criteria, especially given that the trials took place at many hospitals around the world.

Roche turned me down on both fronts. They also refused to give Daniel the R1507 ‘off-trial’ – pharmaceutical companies can, in exceptional circumstances, give a drug to a patient who does not meet the eligibility criteria. This is sometimes called compassionate use: I explain how the system works in the book.

As I also relate in the book, faced with Roche’s intransigence I wrote to the Medicines and Healthcare products Regulatory Agency (MHRA), which approves clinical trials in the UK. I argued that the MHRA should not give the green light to Roche’s eligibility criteria, essentially because the restrictive criteria meant that the maximum benefit would not be derived from the trial for patients, most of whom were children facing a death sentence. This was particularly important with a rare disease like Ewing’s, where information was at a premium. I also contacted the NHS research ethics committee which had to give its approval to the trial as well - every proposal for a clinical trial has to go through both a research ethics committee and the MHRA.

In each case, I used the Human Rights Act, amongst other legal arguments. Article 2 of the European Convention of Human Rights, which the HRA incorporates, guarantees the right to life. We were, sadly, dealing with life and death.

We made some progress following a meeting with Sir John Lilleyman, an oncologist who held a senior position with a body supervising research ethics committees. In the end, my legal arguments fell away because a repeat RT-PCR, carried out in Barcelona, failed to detect any cancer in Daniel’s bone marrow. At the time, that seemed wonderful news but it meant that I could no longer argue that Roche would have a benchmark by which to measure the impact of the R1507. So I had to abandon my struggle for the drug.

That is the background.

In the book, I write:

‘I was forced to the conclusion that desperately ill youngsters such as Daniel count for very little in the grand calculations of drug multinationals. The companies are institutionally and legally geared to sacrificing individuals on the altar of shareholder satisfaction, executive pay and voracious appetite for market share’.

That may seem harsh, but I believe it is fair. Roche could easily have given Daniel the drug, and in the process just possibly save his life. It would have involved them in a little more work, but it would also have provided them with useful information. That in turn would, ultimately, have enabled Roche to make more sophisticated judgements about whether to proceed with the R1507 inhibitor and, if so, for which cancers, and that would have helped them fulfil their legal obligation of maximising returns for their shareholders. But they preferred to keep things bureaucratically easy, to keep to tried and trusted ways of running cancer trials.

In the book, I acknowledge that there are, unquestionably, any number of people who work for drug companies who are dedicated to finding cures for serious diseases and are keen to help individuals in difficult situations where they can. I spoke to quite a few such people during Daniel’s journey. The problem is not individuals but the system, and history teaches that systems and institutional pressures force people to behave in ways they would not behave in different contexts.

I also learnt that drug companies channel cancer drugs to the developing world, at a fraction of the normal cost. This is something they do not publicise. One may wonder, cynically, whether the reason for this unusual coyness is that they do not want to highlight the huge mark-up on drugs sold in affluent countries, but we should nevertheless acknowledge that many people in poor countries benefit from the act of corporate charity.

It is also fair to point that Daniel did eventually get an IGF inhibitor, manufactured by Pfizer. This was under compassionate use. Sadly, by that time, the cancer was too advanced, and too mutated, for the inhibitor to have any real chance of success. But that was not Pfizer’s fault.

However, the charge-sheet against Big Pharma is nevertheless long and serious – much more serious, in fact, than the lack of flexibility and imagination shown by Roche in Daniel’s case.

Anyone reading Bad Pharma, Ben Goldacre’s book, would take prescription medicines only if they had no choice. Many of the themes were not new to me, reflecting things I had read over the years, even before Daniel’s illness. But I was taken aback by the scale and breadth of corruption and unethical behaviour Dr Goldacre described, and the examples he gives. He is a medical doctor who has studied in detail how the pharmaceutical industry works and how it interacts with his own profession. His approach is careful, very much evidence-based. He is no radical when it comes to medical treatment, and has been vocal in his criticism of homeopathy and other examples of what he considers ‘quackery’. He acknowledges that many drugs are beneficial. He is on the side of good science and of clinical practice which serves the interests of patients. So his litany of criticisms should be taken seriously.

They include outright fraud and the systematic withholding of data, especially data showing that a drug does not work or information about serious side-effects. Needless to say, information is crucial not only for doctors and patients but also for regulators who decide whether to grant a drug a licence. Dr Goldacre describes numerous problems with clinical trials, the dubious marketing techniques employed by drug companies and the way they employ ghostwriters to write articles on particular drugs for journals.

Read the article by Melanie Phillips – no card-carrying Leftie – about the corruption of the drug industry in the Times on 4 February 2016, too.

All this I will expand upon in the next blog in this series. I will also discuss the role of regulators and doctors and explain why, in my view, the current R&D model does not work nearly as well as it needs to, both in the developed and developing world. I will then suggest some radical solutions.

A friend of mine, Debbie Binner, will also relate her experience with a drug company. Debbie has faced a double tragedy of unimaginable proportions in the last couple of years: the loss of her 18 year old daughter Chloe to Ewing’s sarcoma and then the assisted suicide of her husband Simon, who choose death over the strangulated decline of motor neurone’s disease.[2]

David Thomas

March 2016

[1] Two important recent books about the problems with the current system are Bad Pharma by Ben Goldacre and Pharmaceuticals, Corporate Crime and Public Health by Graham Dukes, JP Moloney and John Braithwaite, though neither proposes a particularly radical solution.

[2] Debbie’s and Simon’s journey was featured in a documentary on BBC 2 on 10 February 2016

#badpharma #pharmaceutical #drugs #pharmaceuticalindustry #HoffmanLaRoche #IGFinhibitors #insulingrowthfactor #cancer #ewingssarcoma #sarcoma #R1507 #RTPCR #MedicinesandHealthcareproductsRegulatoryAgenc #MHRA #drugcompanies

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